Quaternary ammonium fluorides



United States Patent 3,277,118 QUATERNARY AMMONIUM FLUORIDES Hans Schmid, Muttenz, and Hans Rudolf Miihlemann,

Zurich, Switzerland, assignors to GABA AG, Basel,

Switzerland, a Swiss company No Drawing. Filed Mar. 7, 1963, Ser. No. 263,439 Claims priority, application Switzerland, May 29, 1958,

59,996 The portion of the term of the patent subsequent to Mar. 10, 1981, has been disclaimed 16 Claims. (Cl. 260347.7)

This is a continuation-impart of application Serial No. 815,253, filed May 25, 1959, now US. Patent 3,124,512.

The present invention relates to quaternary ammonium fluorides useful in caries prophylaxis. In recent years research has shown that the element, fluorine, is of considerable importance in the formation of dentin and that a deficiency in this element leads to an increased tendency of the teeth to dissolve in acids, thus reducing the resistance of teeth to caries. Moreover, it is known that the acids responsible for a slow dissolution of dentin are formed by bacterial and enzymatic decomposition of food particles.

By providing a sufliciency of the element, fluorine, the solubility of dental enamel in acids can be significantly reduced, the introduction of fluorine being possible prior to dentition through the medium of the blood and after dentition by external applications. For the latter purpose, fluorine has generally been used in the form of an inorganic, e.g. in the form of an alkali metal fluoride, tin fluoride, silicofluoride and as a complex fluoride of an element of Group IV of the Periodic System (British specification No. 644,339).

It has now been found that certain water-soluble quaternary ammonium fiuorides reduce the solubility of dental enamel in acids to a significant degree. The presence of one or several long-chain radicals in such compounds, moreover, imparts foaming, wetting and, in particular, bactericidal properties to the fluoride. Thus when applied externally in the cavity of the mouth, they are capable of inhibiting the cleavage of carbohydrate-containing remainders of foodstulfs into acidic, enamel-dissolving decomposition products. These long-chain cation-active ammonium fluorides are thus active agents for caries prophylaxis both due to their ability to increase the resistance of dental enamel to the action of acids (fluorine action) and due to their bactericidal activity.

It is an object of this invention to provide compounds for caries prophylaxis, said compounds being water-soluble long-chain quaternary ammonium fluorides which are anti-caries agents. This and other advantages are apparent from application Serial No. 815,253, filed May 25, 1959 (now US. Patent No. 3,124,512), of which this application is a continuation-in-part, and from the following detailed description.

The long chain quaternary ammonium fluorides according to this invention are represented by the following R is alkyl having from 8 to 20, and preferably from 12 to 18, carbon atoms, e.g. octyl, dodecyl and octadecyl;

R may have the same meaning as R; alkenyl having from 8 to 20, and preferably from 12 to 18, carbon atoms and one or more carbon-to-carbon double bonds (either conjugated or non-conjugated), e.g. octenyl, hexedecenyl and eicosenyl; or alkylol having from 8 to 20, and preferably from 12 to 18, carbon atoms, e.g.hyd-roxyoctyl, hydroxytetradecyl and hydroxyeicosyl;

R is alkyl having at most 20 carbon atoms, either straight chain or branched chain, e.g. methyl, isooctyl, dodecyl and eicosyl; lower alkylol, e.g. hydroxymethyl, 'y-hydroxybutyl and hydroxyoctyl; lower alkoxy, e.g. methoxy, pentoxy and octyloxy; (lower alkoxy)-(lower alkyl), e.g. methoxy methyl, methoxy octyl, octyloxy methyl and octyloxy octyl; phenoxy-(lower alkyl), e.g. phenoxymethyl, phenoxybutyl and phenoxyoctyl; carboxymethyl; lower cycloalkyl, e.g. cyclobutyl, cyclohexyl and cyclooctyl; furfuryl; and carbocyclic aryl, e.g. diphenyl, phenyl and naphthyl;

R is lower alkyl, e.g. methyl, ethyl, propyl, butyl, pentyl,

hexyl, heptyl and octyl;

R is lower alkyl as exemplified for R R is alkyl having at most 20 carbon atoms, e.g. methyl,

heptyl, dodecyl, hexadecyl and eicosyl;

R is lower alkylene, e.g. methylene, propylene, octylene;

R is lower alkyl as exemplified for R R is hydrogen or lower alkyl as exemplified for R and X is either sulfur or oxygen.

In each of the preceding definitions and throughout this disclosure lower is employed to define groups having at most eight carbon atoms. In contrast, higher or long chain is used to designate chains (primarily carbon-to-carbon chains) of from eight to twenty carbon atoms.

Each of the compounds represented by Formulae I to V is a water-soluble quaternary ammonium fluoride. For use in caries prophylaxis compositions each of said compounds is best employed in a composition with a fluoride-compatible carrier. The concentration of the quaternary ammonium fluoride in the composition is sufficient to provide from about 0.01% to about 2.0% by weight (based upon the weight of the total composition) of ionizable fluorine.

Quaternary ammonium fluorides according to this invention are hygroscopic crystalline solids or liquids soluble in methanol and ethanol. The long chain substituents are responsible for the formation of foaming aqueous solutions. Said fluorides are incompatible with anionactive compounds, such as alkyl sulfates, alkaryl sulfates and soaps.

Quaternary ammonium fluorides are prepared by quaternizing the corresponding substituted secondary or tertiary amines with an organic fluoride. The secondary J and tertiary amines used as starting materials are obtained byconventional methods. Quaternization is carried out, e.g., by heating with the addition of a solvent or diluent.

4 and octyl; lower alkenyl, e.g. vinyl, allyl, butenyl, octenyl; lower alkylol, e.g. B-hydroxyethyl, y-hydroxypentyl and w-hydroxyoctyl; lower alkoxy, e.g. methoxy and octyloxy; (lower alkoxy)-(lower alkyl), e.g. meth- The more readily accessible corresponding quaternary oxyethyl, ethoxylhexyl, heptoxybutyl and pentoxyproammonium chlorides or bromides can also be used for pyl; phenoxy-(lower alkyl), e.g. phenoxymethyl and preparing the quaternary ammonium fluorides. The chlophenoxyoctyl; furfuryl; carboxymethyl; carbocyclic (at ride or bromide is reacted in the presence of a solvent most bicyclic) aryl, e.g. phenyl, diphenyl and naphthyl; with a simple metal fluoride in such a manner that the or lower cycloalkyl, e.g. cyclopropyl, cyclopentyl, cyclometal chloride or bromide formed in the reaction prehexyl and cyclooctyl; or lower cycloalkyloxy lower cipitates from the solvent. For this purpose metal fluoalkyl, e.g. carbocyclohexoxyethyl. rides are used which are more soluble in the selected R represents lower alkyl, e.g. methyl, propyl, amyl and solvent than the corresponding chloride or bromide. The octyl; lower al'kenyl, e.g. ethenyl, pentenyl and octenyl; quaternary ammonium fluoride formed during the reaclower alkyloLleig. methylol and hydroxyoctyl; or lower tion remains in solution from which it can be recovered alkoxy, e.g. methoxy and octyloxy. by conventional methods after removal of the insoluble R represents one of the radicals of R naphthyl or salt. Potassium fluoride or silver fluoride is preferably phenoxyethyl. employed. The reaction with potassium fluoride is, e.g., 1 carried out in ethanol, aqueous ethanol, an ethanol-acefi i i quatefnary ammonium fluorides according tone mixture or a water-acetone mixture. The reaction to t 15 mventlon with silver fluoride proceeds in an aqueous medium. octy1 trimthy1 ammonium fl id The quaternary ammonium fluorides are mixed with 1 h l d h l i fl id conventional solid or liquid diluents and other additives, octadecylqnethypdiethanopammonium fl id such as abrasive agents, fillers, binders, solvents and dilaury1 dimethy1 ammonium fl id fl g agem 5, order P R F compositions A -octadecenyl-naphthyl-dimethyl-ammonium fluoride, mg a high caries prophylact1c activity. These composidioctyl diethyl ammonium fluoride,

trons are prepared in the form of tooth paste or powder, cyclohexyl cetyl dimethypammonium fl id mouth wash, lozenges or tablets and dental preparations f f 1 1 1 di th 1 i .fl -id for use 111 'y- V phenoxyethyl-cetyl-dimethyl-ammonium fluoride,

A group of compounds of the present invention are N (z ethoxy ethyl) N dodecypdimethypammonium those of Formula I. fl o id wherein N-(fi-hydroxydodecyl)-trimethyl-ammonium fluoride, R represent s a high molecular hydrocarbon radical hav- N-phenyl-N-hexadecyl-diethyl-ammonium fluoride,

mg a chain length of from C to C either saturated, N-cyclohexyl-N-octadecyl-dimethyl-ammonium e.g. octyl and eicosyl, or ethylenically unsaturated, e.g. fluoride,

decenyl and nonadecenyl. The radical is preferably N-(2-carboeyclohexoxyethyl)-N-myristyl-dimethylfrom C to C e.g. dodecyl, hexadecenyl and octaammonium fluoride,

decyl. R as defined above, may also be substituted, N-(Z-carbgphenoxyethyl) N-dodecyl.dimethyle.g eicosoate, mercaptohexadecyl and aminododecyl, ammonium fluoride, and

or interrupted, e.g. butoxyhexadecyl, hexylthiodecyl and NscarboXymethy1 N eioSy1 dimethy1 ammonium pentylamlnopropyl, by a hetero atom, e.g. oxygen, sulfl id fur and nitrogen, or groups such as CO, e.g. octylketobutyl. Additional examples of quaternary ammonium fluo- R has the same meaning as R or represents lower alkyl, rides according to this invention are those of Formula e.g. methyl, ethyl, propyl, butyl, isopentyl, hexyl, heptyl I wherein R R R and R are as enumerated in Table 1.

. TABLE 1 Compound R R R R4 1 H(CHa)a- HaC- H2C=CHCH=CH H30 2. H(CHz)n H(CH2)8- H(CH2)sO CH HxC\ H30 3 H(C 2)1a /CH HsC=CH(CHg)s- 11 0-- BIG 4 H(CHz):0 H:C=CH HO-(CHQF H1C=CHCH=CH 5 3,7-dimetl1yl-2,64Jetadienyl HzC=CH-(CH5)- H(CHn)a- H(CH;):O

6 l-dodecenyl H3C CHOH HaCO O(CH7):

7 9,12,15-0ctadecatrienyl HO--(CHz)a H(CH1)5 HO=CH,(CH1) 8 Arachidouyl HaCO-CH2 HO-CHg- HO-(CH 9 HaN(CH2)10 HaCO(CH2)a- H2C=CH(CH:): H(CH)5 10 HS(CH2)m- H(CHa)x0-CHs- H(CHa): HaC-O 11 HOOC(CH:)m H(CH2)s-O(CH2)s HaC-CHOHCH: H(CH1)5 TABLE 1'Continued Compound R R R R 12 H(CH2)4O-(CH2)1r- H2C=CH HO-CH 13 H(CH2)aS(CH2)i0 H(CH2)4O H2C=CH(CH2)3 H30 14 H(CH2) -NH(CHz)3 \CH HaC-CHOH-CHz 15 H(CH2)sCO(CH2)4- Cyclohexyl HzC H2C=CH 16 H(CH2)s- HaC-O- H2C=CH(CHz)s O(CHz)z 11 H(oH2),= G o-01a? HzC=CH H- HS(CH2)1z H(CHz)x,-O H(CH2)3 HO(CH2)s H(CHz)1s Furfuryl HO(CH2)s H(CH2)4O Oleyl UO(CH2)B HsC-O H(CH2)3 21 H(CH2)20 H3CCO HOCH2- The quaternary ammonium fluorides of Formula I are prepared in the same manner as set forth in Examples 1 and 2.

Example 1 To 101 parts by Weight of triethylamine are added, while stirring, 188 parts by weight of dodecyl fluoride, and the mixture is maintained at C. for 6 hours. On cooling of the reaction mixture to 20 C., the produced dodecyl-triethyl-ammonium fluoride is obtained in the form of a hygroscopic crystalline mass. This compound is soluble in water, ethanol and methanol.

Example 2 30.4 parts by weight of lauryl-phenyl-methyl-ethyl-ammonium bromide are dissolved in 200 parts by weight of water, and to the solution is added an aqueous solution of 12.7 parts by weight of silver fluoride. The precipitated silver bromide is filtered 011?, and the filtrate is concentrated in vacuo whereby lauryl-phenyl-methylethyl-ammonium fluoride remains as a syrupy liquid which begins to crystallize after standing for a prolonged period.

The long-chain quaternary ammonium fluon'des are used in caries-prophylaxis compositions in concentrations suflicient to provide from about 100 to about 7500 parts of fluoride per million parts of the compositions. If the composition is of the type ordinarily applied by a dentist, such as an aqueous topical solution or prophylaxis paste, concentrations suflicient to provide from about 100 ppm. to about 7500 ppm. of fluoride are used. In toothpaste, toothpowder, mouthwash and the like, the concentration should be suflicient to provide from about 100 p.p.m. to about 4000 p.p.m. of fluoride ion. Preferably, products intended for frequent use in the home contain a quantity of the long-chain quaternary ammonium fluorides suflicient to provide from about 500 ppm. to 3000 ppm. of fluoride ion. 7

The pH of the compositions are preferably within the range from about 3.5 to 7.0 while in contact with the teeth. Above about pH 7.0 the effects of fluoride ion in reducing enamel solubility diminishes. Below about pH 3.5 undesirable alteration of the tooth structure can occur. Preferably the pH of these compositions is in the range from about 3.8 to about 5.5 while in contact with the teeth.

Acidifying agents which are suitable for use in the oral cavity can be used to adjust and maintain the pH of the composition within the desired range. Suitable acidifying agents include, for example, acetic acid, citric acid, sodium or potassium dihydrogen phosphate, and hydrochloric acid.

In addition to the quaternary ammonium fluorides the compositions of the present invention may contain conventional additives which are not anion-active. In view of the fact that the fluorine is partially deactivated by the more commonly used abrasives, such as calcium carbonate, magnesium carbonate, dicalcium orthophosphate, calcium sulfate, kaolin, etc., it is preferable to use fluoride compatible abrasives, such as the oxides, orthoor pyrophosphates of tin or zinc, in the compositions. Moreover, the dental compositions may also contain surfaceactive substances of non-ionic or cation-active nature as forming and cleansing agents as well as flavoring agents. In paste-like dental compositions mucila-ges of non-ionic nature are conveniently used.

Some examples of caries prophylaxis compositions are given hereinafter by way of non-limiting illustration.

Example 3.Tooth Paste Percent Ingredients: by weight Zinc phosphate 20.0 Titanium dioxide 2.0 Glycerol 12.0 Methyl cellulose 3.0 Flavoring agent 1.0

Dodecyl-trimethyl-ammonium fluoride 1000 p.p.m. F-) 1.3 Water 60.7 pH 5.0 (adjusted with HCl).

The methyl cellulose is dissolved in part of the water.

to form a mucilage whereupon the quaternary ammonium fluoride, dissolved in the remaining amount of water, is added. Then glycerol, the flavoring agent and finally the powdered ingredients are incorporated. The mass is thoroughly mixed in a suitable mixer and, if necessary, homogenized in a roller or colloid mill.

This composition is effective for use in caries prophylaxis and has acceptable consumer properties. It is stable and remains active for long periods of time under normal conditions of storage. The dodecyl-trimethyl-ammonium fluoride employed in this example may be replaced by octadecyl-methyl-diethanol-ammonium fluoride, phenoxyethyl-cetyl-dimethyl-ammonium fluoride, A -octadecenyltriethyl-ammonium fluoride, dioctyl-dimethyl-ammoniurn fluoride and N (13 hydroxy dodecyl) trimethylammonium fluoride, for example, in quantities suificient to provide the same level of fluoride ion with no substantial loss of the beneficial properties of the composition.

Effective jelly-like dentifrice compositions can be prepared by omitting the abrasive ingredient and incorporating a small proportion of titanium dioxide, for example, as a pigmenting agent. This is illustrated in the following example.

Example 4 Percent Ingredients: by weight Titanium dioxide 2.0

Mucilage jelly from powdered fruit-kernels 79.57

Glycerol 16.0 Saccharin 0.1 Flavoring agent 1.0 Lauryl phenyl trimethyl ammonium fluoride (750 p.p.m. F) 1.33

pH 5.5 (adjusted with acetic acid).

without loss of the desired anticaries properties, as long a as the total fluoride content is at least as great.

Example 5 A mouth wash having the following composition is prepared:

Dodecyl ethyl dimethyl ammonium fluoride (7500 p.p.m. F-) 10.25

Prior to use, this composition is diluted, e.g. by adding 2 ml. of the concentrate to 50 ml. of water, to obtain a fluorine concentration of 300 p.p.m.

The quaternary ammonium fluoride is dissolved in ethyl alcohol. Glycerol and the flavoring ingredients are added to this solution. When used with suflicient frequency this mouthwash provides an excellent caries prophylactic.

N carboxymethyl N eicosyl dimethylammonium fluoride, N (5 hydroxy dodecyl) triethanol-ammonium fluoride, octyl-trimethyl-ammonium fluoride, and stearyl-phenyl-dimethyl-ammonium fluoride can be used in conjunction with or in place of the dodecyl-ethyldimethyl-ammonium fluoride employed in this example without loss of the desired properties.

Example 6 A toothpowder may be prepared as follows- Percent Ingredients: by weight Zinc pyrophosphate 96.32 1 Flavoring agent 1.0

Phenoxyethyl cetyl dimethyl ammonium fluoride (1000 p.p.m. F-) Citric acid Zinc pyrophosphate and citric acid are well mixed with the quaternary ammonium fluoride in a suitable mixer.

The mixture is, if necessary, finely ground, and finally the flavoring ingredient is stirred in. This composition is stable and is effective in inhibiting caries formation.

Although the foregong exemplification of dental com- 1 positions for caries prophylaxis is directed to products Which are ordinarily used in the home, it is to be understood that compositions that are usually applied by the dentist are also contemplated. For example, a dental prophylaxis paste containing the usual pumice and flavor- 1 justed to a pH within the range of 3.5 to 7.0 with any of the hereinbefore acidifying agents, may be topically applied to the teeth by the dentist. Such compositions may also contain, e.g., flavoring materials.

A second group of compounds (according to the present invention), which reduce the solubility of dental enamel in acids, includes heterocyclic ammonium compounds containing at least one quaternary nitrogen atom with anionically bound fluorine. Among these compounds are pyridinium compounds of Formula II wherein R represents alkyl from 8 to 20 carbon atoms and preferably from 12 to 18 carbon atoms, e.g. octyl, dodecyl, octadecyl and eicosyl; alkenyl from 8 to 20 carbon atoms and preferably from 12 to 18 carbon atoms, e.g. octenyl, hexadecenyl and eicosenyl; alkylol having from 8 to 20, and preferably from 12 to 18, carbon atoms, e.g. hydroxyoctyl, hydroxytetradecyl and bydroxyeicosyl; alkoxyalkyl having a total of at most twenty carbon atoms, including (lower alkoxy)-(lower alkyl), e.g. methoxymethyl, ethoxyoctyl, propoxyheptadecyl, hexadecyloxybutyl, dodecyloxyamyl, decyloxynonyl, and octyloxymethyl; carbocyclic ar(lower)alkyl, e.g. 4-phenylbenzyl, phenylethyl and u naphthyl-3- propyl; lower cycloalkyl, e.g. cyclopropyl, cyclohexyl and cyclooctyl; or heterocyclic, e.g. furfuryl, morpholino, thiomorpholino, picolino, piperidino, pyrrolidino quinolino and indolino.

The preferred compounds of Formula II are those wherein R is alkyl, especially alkyl with from 12 to 18 carbon atoms.

Examples of quaternary ammonium fluorides of Formula H are:

N-cetyl-pyridinium fluoride, N-dodecyl-pyridinium fluoride, N-octadecyl-pyridinium fluoride, N-octyl-pyridinium fluoride, N-eicosyl-pyridinium fluoride, N-3,7-dimethyl-2,6-octadienyl-pyridinium fluoride, N- l-dodecenyl-pyridinium fluoride, N-9,12,15-octadecatrienyl-pyridinium fluoride, N-arachidonyl-pyridinium fluoride, N-u-hydroxyoctyl-pyridinium fluoride, N-9-hydroxytetradecyl-pyridiniurn fluoride, N-w-hydroxyeicosyl-pyridinium fluoride, N-methoxymethyl-pyridinium fluoride, N-ethoxyoctyl-pyridinium fluoride, N-propoxyheptadecyl-pyridinium fluoride, Ncetyloxybutylpyridinium fluoride, N-dodecyloxyamyl-pyridinium fluoride, N-decyloxynonyl-pyridiniurn fluoride, N-octyloxymethyl-pyridinium fluoride, N-4-phenylbenzyl-pyridinium fluoride, N-phenylethyl-pyridinium fluoride, N-a-naphthyl-3 -propyl-pyridinium fluoride, N-cyclopropyl-pyridinium fluoride, N-cyclohexyl-pyridinium fluoride, N-cyclooctyl-pyridinium fluoride, N-furfuryl-pyridinium fluoride, N-morpholino-pyridinium fluoride, N-thiomorpholino-pyridinium fluoride, N-picolino-pyridinium fluoride, N-piperidino-pyridinium fluoride, V N-pyridino-pyridinium fluoride, N-pyrrolidino-pyridinium fluoride, N-quinolino-pyridinium fluoride, and N-indolino-pyridinium fluoride.

The quaternary ammonium fluorides of Formula II are prepared in the same manner as set forth in Example 7.

Example 7 79 parts by weight of pyridine are dissolved in 750 parts by weight of ethanol. The resulting solution is added, while stirring, to 244 parts by weight of cetyl fluoride at 50 C. The mixture is then refluxed for two hours, and the solvent is thereafter evaporated. The residue consists of cetyl-pyridinium fluoride which is in the form of a crystalline mass which is soluble in water, methanol and ethanol.

Compounds of Formula H are advantageously employed in dental compositions in the same manner and for the same purpose as those of Formula I. An exemplary dental composition is:

Example 8.T00th paste Percent Ingredient: by weight Zinc phosphate 20.0 Titanium dioxide 2.0 Glycerol 12.0 Methyl cellulose 3.0 Flavoring agent 1.0

N-cetyl-pyridinium fluoride (corresponding to 0.1% F) 1.7 Water 60.3

The methyl cellulose is dissolved in part of the water to form a mucilage whereupon the quaternary ammonium fluoride, dissolved in the remaining amount of water, is added. Then glycerol, the flavoring agent and finally the powdered ingredients are incorporated. The mass is thoroughly mixed in a suitable mixer and, if necessary, homogenized in a roller or colloid mill.

The pH of tooth paste compositions is between 3.5 and 7.0, preferably between 3.8 and 5.5. The proportion of quaternary ammonium fluoride, calculated as fluorine, is 0.01 to 2.0%, preferably 0.05 to 0.3%, by weight. With these considerations in mind, any non-toxic quaternary ammonium fluoride of Formula II can be employed, either singly or in combination, in tooth paste formulations similar to that of Example 8.

Further heterocyclic quaternary ammonium compounds according to this invention are the morpholinium and thiomorpholinium fluorides of Formula III wherein X is oxygen or sulfur;

R represents alkyl having from 8 to 20, preferably 12 to 18, carbon atoms, e.g. octyl, dodecyl, ,octadecyl, eicosyl; alkenyl from 8 to 20, preferably from 12 to 18, carbon atoms, e.g. octenyl, hexadecenyl and eicosenyl; alkylol having from 8 to 20, preferably from 12 to 18, carbon atoms, e.g. hydroxyoctyl, hydroxytetradecyl and hydroxyleicosyl; alkoxyalkyl having a total of at most twenty carbon atoms, including (lower alkoxy)-(lower alkyl), e.g. methoxymethyl, ethoxyloctyl, propoxyheptadecyl, cetyloxybutyl, dodecyloxyamyl, decyloxynonyl and octyloxymethyl; carbocyclic ar(lower)alkyl, e.g. 3-phenylbenzyl, phenylpropyl and and B-naphthyl-Z-ethyl; or lower cycloalkyl, e.g. cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl.

R represents one of the radicals defined above as R or lower alkyl, e.g. methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl and octyl.

Preferred compounds of Formula III are those wherein both R and R are alkyl, particularly alkyl having from 8 to 20, especially from 12 to 18, carbon atoms. Examples of quaternary ammonium fluorides of Formula III are those wherein X, R and R are as enumerated in Table 2.

TABLE 2 Com- X R R X Compound pound 1 Oxygen-.- Eicosyl Su1lu.r 35 d d 36 37 38 39 40 41 42 43 Cyclopropyl do 44 fl-Naphthyl-Zethyl do 45 l Octyloxymethyl do 46 Octadecyl Methoxymethyl d 47 Eicosyl w-HydroxyeicosyL- 48 3,7-dimethy1-2,6-octadienyl Decy1oxynony1 49 l-dodecenyl Eicosyl 50 9,12,15-octadecatrienyl. Oyclohexyl 51 a-Hydroxyoctyl Phenylpropyl 52 Q-hydroxytetradecyl. Octadecy1 53 wHydroxyeicosyl Cyclopentyl 54 Methoxymethyl 3-phenylbenzyl 55 TABLE 2Continued R R; X Compound Ethoxyoctyl Dodecyloxyam l do 56 Propoxyheptadecyh Q-hydroxytetradecyl. do 57 Cetyloxybutyll-dodecenyl do 58 Dodecyloxyarnyl Cetyldo 59 Decyloxynonyl. CyclooctyL do 60 Octyloxymethyh. Oetyloxybutyl do 61 3-phenylbenzyl Propoxyheptadecyl do 62 Phenylpropyl 3,7-dtmethyl2,6-octadicnyl do 63 fl-Naphthyl-Zethyh. Dodecyl do 64 CyclopropyL EthoxyoctyL... do 65 CyclopentyL. a-Hydroxyoctyl do 66 Cyclohexyl 9,12,15octadecatrienyl do 67 Cyclooctyl Octyl do 68 In Table 2 the number of the compound is given in the left column when X is oxygen and in the right column when X is sulfur. The quaternary ammonium fluorides of Formula III are prepared in the same manner as is exemplified in Example 9.

Example 9 11.5.2 parts by weight of N-ethylmorpholine and 214.4 parts by weight of myristylfluoride are dissolved in 100 parts by weight of toluene.

The solution is allowed to stand over night, whereupon it is heated for 3 hours at 110 C., is again allowed to stand for 12 hours, whereafter the reaction mass can be worked up as follows, either:

(a) Precipitated crystals of the quaternary ammonium compound are filtered oil, then dissolved in ether and the ether solution is extracted with water. The aqueous solution is exaporated to dryness in vacuo and the tetradecyl-ethyl-morpholinium-fluoride obtained as residue or:

(b) The entire reaction mass is dissolved in ether, the ether solution is extracted with water and the aqueous solution is evaporated as under (a).

Compounds of Formula III are advantageously employed in dental compositions in the same manner and for the same purpose as those of Formula I. Exemplary dental compositions are:

Example A mouth wash having the following composition is prepared:

Percent Ingredient: by weight Ethyl alcohol 64.28 Glycerol 12.00 Flavoring agent 6.00 NzN-dilauryl-morpholinium fluoride 17.72

Prior to use this composition is diluted, e.g. by adding 2 ml. of the concentrate to 50 ml. of water, to obtain a fluorine concentration of 0.03% by weight.

The quaternary ammonium fluoride is dissolved in ethyl N myristyl N-ethyl-morpholinium fluoride (corresponding to 0.1% F) 1.73 Citric acid 0.5

Zinc pyrophosphate and citric acid are well mixed with the active ingredient in a suitable mixer. The mixture is finely ground. Finally the flavoring is stirred in.

A fourth group of compounds (according to the present invention), which reduce the solubility of dental enamel in acids, encompasses those of Formula IV wherein R, R and R are as initially presented immediately following Formula IV. Exemplary quaternary ammonium fluorides are those of Formula IV wherein R, R and R are as enumerated in Table 3.

TABLEB Compound R R R Methyl- Octyl.

EthyL. Heptyl.

PropyL Hexyl.

Butyl Pentyl.

myl Butyl.

HexyL. Propyl Heptyl Ethyl.

Eicosyl Octyl Methyl The quaternary ammonium fluorides of Formula IV ample 12.

Example 12 61.44 parts by weight of N:N'-tetramethyl-N:N-dilauryl-ethylene-diammonium-dibromide are dissolved in 200 parts by weight of absolute ethyl alcohol. To this solution is added 11.62 parts by weight of potassium fluoride.

The mixture is boiled under reflux for 5 hours, allowed to stand for 12 hours and filtered off from the potassium bromide formed. The filtrate is evaporated in vacuo. NzN' tetramethyl N:N'-dilauryl-ethylene-diammoniumdifluoride remains as residue.

Compounds of Formula IV are advantageously employed in dental compositions in the same manner and for the same purpose as those of Formula I. An exemplary dental composition is:

Example 13 A mouth wash having the following composition is prepared:

Percent Ingredient: by weight Ethyl alcohol 72.2

Glycerol 12.0

Flavoring agent 6.0 N:N' tetramethyl N:N'-dilauryl-ethylene-diammonium difluoride 9.8

Prior to use this composition is diluted, e.g. by adding 2 ml. of the concentrate to 50 ml. of water, to obtain a fluorine concentration of 0.03% by weight.

The quaternary ammonium fluoride is dissolved in ethyl alcohol. Glycerol and the flavoring ingredient are added to this solution.

Another group of compounds according to this invention includes derivatives of amino acids comprising a quaternary ammonium group and being represented by Formula V wherein R represents alkyl from 8 to 20 carbon atoms and preferably from 12 to 18 carbon atoms, e.g. octyl, dodecyl,

octadecyl and eicosyl; alkenyl from 8 to 20 carbon atoms and preferably from 12 to 18 carbon most twenty carbon atoms, including (lower alkoxy)- (lower alkyl), e.g. methoxymethyl, ethoxyoctyl, propoxyheptadecyl, hexadecyloxybutyl, dodecyloxyamyl, decyloxynonyl and octyloxymethyl; carbocyclic ar- (lower) -alkyl, e.g. 4-pheny1benzyl, phenylethyl and a-naphthyl-3-propyl; lower cycloalkyl, e.g. cyclopropyl, cyclohexyl and cyclooctyl; or heterocyclic, e.g. furfuryl, morpholino, thiomorpholino, picolino, piperidino, pyrrolidino, quinolino and indolino.

R represents one of the R radicals or lower alkyl, e.g.

methyl, amyl and octyl.

R represents one of the R radicals.

octyl; or heterocyclic, e.g. furfuryl, morpholino, thiornorpholino, picolino, piperidino, pyrrolidino, quinolino and indolino.

R represents one of the meanings of R R represents lower alkylene, e.g. methylene, ethylene,

isopropylene, octylene; or carbocyclic arylene(lower) alkylene, e.g. 2-phenylene-ethyl, paradiphenylene-propyl and l-naphthylene-4-methyl.

15 enumerated in Table 4.

Exemplary quaternary ammonium fluorides of Formula V are those wherein R, R R R R and R are as TABLE4 Com- 1 2 3 4 pound Dodeeyl Cetyl Octadecyl. 4-phenylbenzyl a-HydroxyoetyL- Furfuryl. Piperidino Cyclopropyl Arachidonyl.

2-pl1enyleneethyl Heptylenp Ethylene. Vin Dipheuyl Furfuryl. Isopropyl Indolino Cyclooetyl.

Com- 6 6 7 8 pound Eicosyl 3,7-dlmethyl-2,6-octadienyl l-dodecenyl 9,12,15-octadecatrienyl. Methoxymethyl Ethyl Dodeeyloxyamyl. Decyloxynonyl. Pimlinn Heptyl Furruryl Dodecyl. Octylene Hexy1ene Propy 1-naphthylene-4-methyl. Methyl Ally] Naphthyl Morpholino. Phenyl Octyl Quinolino Cyclohexyl.

Com- 9 10 11 12 pound Arachidonyl a-HYdIOXYOCtYl Q-hydroxytetradeeyl wHydroxyeicosyL Morpholino- Propyl Pyndmo Octyloxymethyl. Octyloxymethyl Hexyl Cet Morpholino.

Pentylene Isopropylene Octylen Methylene. Eth Butadieny1-1,3 4-phenylbenzyl Thiomorpholino. w-Hydroxyoctyl Heptyl Pyrrolldino Cyclopropyl.

Coml3 14 15 16 pound Methoxymethyl Ethoxyoctyl Propoxyheptadecyl Hexadecyloxybutyl. Butyl Picolino 4-phenylbenzyl Isopropyl.

l-dodecenyL Phenethyl Amyl. Paradiphenylene-propyl- Ethylene Pentylene. Octenyl-l- Phenethyl Picolino. Hexyl Piperidino fi-Naphthyl-iS-propyl.

Oom- 17 18 19 20 pound Dodecyloxyamyl Decyloxyononyl OctyloxymethyL- 4phenylbenzyl. w-HydroxyeicosyL Eicosyl Piperidlno r Pentyl. Pyridino Cylooetyl 9,12,15-octadecatrienyl Butyl. Heptylene. Butylone Hexylene Propylene. Butyl Methylol B-naphthyl-3-propyl Piperldino. Methylnl Am Pienlinn Phenethyl.

Com- 21 22 23 24 pound Phenethyl a-Naphthyl-3-propyl Cyclopropyl Cyclohexyl. Cyclopropyl- 1-dodecenyl- Hexyl B-Naphthyli-propyl. Ethoxyoetyl Cyclopropyl Propyl Eicosyl. Ethylene Heptylpne Methylene Paradiphenylenepropyl.

Amyl B-hydroxypropyl CyclopropyL- Pyrrolidino.

Com- 25 26 27 28 29 pound Cyclooctyl Furfuryl- Morphn Thiomorpholino Pyridine. Quinolino Heptyl Methoxy-methyl Ethoxyoctyl Arachidonyl. Decyloxynonyl Ethyl fl-Naphthyl-Zi-propyL. 3,7-dtinethyl-2fi- Methoxymethyl.

00 a leny Hexylene Octylene Pentyle Isobutylene Butylene. Hexyl w-Hydroxyoctyl Cyelohexyl Quin0lin0 Heptyl,

Butadienyl-1,3 Propyl Morpholino Naphthyl Ethyl.

TABLE 4-Continued Com- 30 31 32 33 34 pound Plcolin Piperidino Pyrrolldino Quinolino Indolino. Cetyl Ethxy0ctyl Cyclohexy Dodeeyl Oct 9-hydroxytetradecyl 4-phenylbenzyl Indolino i Cyclooctyl Methyl.

Propylene Ethylene l-nap'glthlylene-- Methylene 2-phenyleneethyl.

me y Phenyl Cyclooctyl Indolino Octy1 Hydrogen. llyl Furiuryl Diphenyl Vinyl Methyl.

The quaternary ammonium fluorides of Table 4 are (IX), s E prepared in the same manner as set forth in Example 14. H(|)/ (I? F Exam le 14 HO 0 CH p ofi r f 50.55 parts by weight of N-[2-(N:N'-dimethylaminocarbonyl)-ethyl]-N-octadecyl-diethyl-ammonium bromide R are dissolved in 350 parts by weight of water. An aque- (X) CH CH ous solution of 12.7 parts by weight of silver fluoride is added thereto and the mixture is heated for 15 minutes H0 0 at 60 0. H3; l

After cooling, the precipitated silver bromide is filtered off and the filtrate is evaporated to dryness in vacuo.

N- [2- (N' N-dimethyl-aminocarbonyl -ethyl -N-octadecyl-diethyl-ammonium fluoride remains as residue.

Compounds of Formula V are advantageously employed in dental compositions in the same manner and for the same purpose as those of Formula I. An exemplary dental composition is:

Example 15 A mouth wash having the following composition is prepared- Percent Ingredient: by weight Ethyl alcohol 67.6 Glycerol 12.0 Flavoring agent 6.0

N- [2- (N' N-dimethylaminocarbonyl -ethyl] N-dodecyl-diethyl-ammonium fluoride 14.4

Glycerol and the flavoring are added to Examples of compounds of Formulae VI and IX are those wherein R has each of the meanings enumerated in Table 2. Examples of compounds of Formulae VII,

VHI and X are those wherein R and R are, respectively, each of the matching pairs enumerated in Table 2. All

of the resulting quaternary ammonium fluorides are advantageously employed in dental compositions in the same manner and for the same purpose as those of Formula I. Compounds of Formulae VI through X are prepared in the same manner as set forth in Example 9.

It is understood that the present invention is in no way limited to the specific examples herein. Various other quaternary ammonium fluorides of this invention can be substituted for those specifically identified in the examples.

What is claimed is:

1. A compound of the formula R is a member selected from the group consisting of alkyl, alkenyl, and alkylol, having from 12 to 18 carbon atoms; R is a member selected from the group consisting of alkyl and alkenyl having from 12 to 18 carbon atoms,

phenoxy-(lower alkyl), furfuryl, carboxymethyl,

phenyl, diphenyl, naphthyl, lower cycloalkyl and (lower cycloalkyloxy) (lower alkyl) R is a member selected from the group consisting of lower alkyl, lower alkenyl, lower alkylol and lower alkoxy; and

R is a member selected from the group consisting of lower alkyl, lower alkenyl, lower alkylol, lower alkoxy, naphthyl and phenoxyethyl;

10. N- (B-hydroxy-dodecyD-N triethanol ammonium fluoride.

11. N-(Z-ethoxyethyD-N-dodecyl dimethyl ammonium fluoride.

12. N-(w-hydroxy-dodecyl)-trimethyl-ammonium fluoride.

13. N-phenyl-N-hexadecyl-diethyl-ammonium fluoride.

14. N-cyclohexyl-N octadecyl dimethyl ammonium fluoride.

15. N-carboxymethyl-N-eicosyl-dimethyl ammonium fluoride.

16. Dodecyl-tfiethyl-ammonium fluoride.

References Cited by the Examiner UNITED STATES PATENTS 15 9/1942 Shelton 260247 X 18 10/ 1954 Wojcik 260247 12/ 1956 Lichtenwalter et a1. 260567.6 3/ 1958 Miller 260290 4/1961 Bauwin 260247 X 3/1964 Schmid et a1. 16793 OTHER REFERENCES Tsen'g et aL: Chem. Abst., vol. 31, (1937) 001. 655.

ALEX MAZEL, Primary Examiner.

NICHOLAS S. RIZZO, Examiner.

H. R. JILES, Assistant Examiner. 

1. A COMPOUND OF THE FORMULA 